Abstract Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Previous studies have reported that genetic susceptibility is associated with NPC. Jab1/CSN5 promotes cell growth and proliferation. Recent studies have shown that Jab1/CSN5 is aberrantly expressed, is correlated with low expression of p27, and is associated with advanced tumor stage and poor prognosis in several human cancers. In this study, we examined the functional role and correlation between Jab1/CSN5 and p27 protein expression in NPC tissue samples and cell lines, the association of their expression with clinical outcome and the antitumor effects of cisplatin in NPC cells. Immunohistochemical analysis showed that Jab1/CSN5 aberrant expression was inversely associated with p27 expression in NPC tissue samples, and Jab1/CSN5 overexpression was correlated with poor survival (p<0.01). Further analysis showed that Jab1/CSN5 mediated p27 degradation in a proteasome-dependent manner, and Jab1/CSN5 directly interacted with p27 in NPC cells. In addition, inactivation of Jab1/CSN5 by small interfering RNAs resulted in a remarkable increase in p27 levels and in the inhibition of cell proliferation, thereby indicating that Jab1/CSN5 controls the stability of p27 by targeting it for degradation in NPC. Moreover, suppression of Jab1/CSN5 enhanced the antitumor effects of cisplatin in NPC cells. To our knowledge, these findings are the first to suggest that Jab1/CSN5 overexpression is involved in NPC pathogenesis via Jab1-mediated p27 degradation, thus explaining the low p27 levels seen in NPC. Therefore, Jab1/CSN5 could be a diagnostic marker and a novel therapeutic target in patients with NPC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1855. doi:1538-7445.AM2012-1855